The rational design of opioid drugs requires a detailed understanding of the precise interactions between opioid ligand and opioid receptor that underlie ligand selectivity for a particular opioid receptor and that distinguish agonist from antagonist function. During the current grant period our efforts to gain that understanding have focused on the refinement and validation of models of ligand/receptor complexes for the mu and delta opioid receptors (MOR and DOR) and elucidation of the precise features of ligand-receptor interaction that differentiate binding to MOR and DOR. In the next grant period, we propose to extend these studies by applying the insights gained from initial cyclic KOR (kappa opioid receptor) peptide ligands that display high affinity but are nonselective, and from our ligand-receptor interaction models for MOR, DOR, and KOR to design new KOR ligands within the same series that achieve KOR selectivity through KOR-specific receptor interactions. We will also begin a similar process of structure based ligand design for the orphan receptor, ORL1, using a cyclic pentapeptide scaffold. If successful, these studies would represent the considerable achievement of structure-based design of structurally related selective ligands for all 4 classes of opioid receptors, two of which (KOR and ORL1) typically bind only larger peptide ligands. Further, we will follow-up exciting initial results that point to features that determine efficacy. Success in these studies would be a clear indicator of the accuracy of the ligand/receptor interaction models and the applicability of our approaches to a wide array of GPCRs. Finally, we will continue our efforts aimed at transferring peptide-derived pharmacophore information to peptidomimetic scaffolds that hold much greater potential as possible CNS active clinical agents. PUBLIC HEALTH RELEVANCE: The interaction of opioid drugs with their protein targets initiates the desirable and undesirable effects of these drugs. Gaining a precise understanding of these interactions is the first step toward the design and development of opioid drugs with more tailored actions, especially opioids with reduced tolerance, dependence liability, and abuse potential.